The administration of cytokines has been associated with a variety of effects on many organ systems. The mechanism for the cytokine-induced inhibition of hepatic drug metabolism remains unknown. In order to elucidate the role of immunomodulators such as cytokines in vaccine- induced hepatoxicity, purified cytokines have been administered to mice. The effects of these agents have been compared to those of poly I:C, a known interferon inducer, and vaccines. Interleukin 2 caused dose-and time-dependent increases in hexobarbital- induced sleep times. This effect was increased by coadministration of interferon a (IFN a) at doses in which IFN had no effect alone. Interleukin 1 and interferon g (IFN g) also increased sleep time significantly, however administration of tumor necrosis factor caused very modest changes (30% or less). Mice treated with gamma irradiation prior to administration of the cytokines had markedly reduced increases in hexobarbital-induced sleep time when compared to nonirradiated controls. This supports a role for T cells in the toxicity induced by cytokines. Athymic nude mice showed similar effects. IL 2 and IL 2 plus IFN a produced much smaller increases in hexobarbital-induced sleep time when compared to normal mice similarly treated. In contrast, the effects of DTP vaccine were similar in all three groups of mice, suggesting that an alternate pathway for the increased sleep times may be possible. To evaluate the effects of the cytokines on hepatocytes specifically, several lines of hepatoma cells have been cultured. These have been treated with cytokines and other agents. RNA has been isolated and is being processed in order to determine at the molecular level how these agents alter drug metabolizing enzymes.